ES2857821T3 - Preparation process of 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3 -methyl carboxylate - Google Patents

Abstract

Preparation procedure of the compound of the formula (I) ** (See formula) ** by reacting the compound of the formula (II) ** (See formula) ** with a metal cyanate of the formula (III) MeOCN in where Me is Li, Na, K or Cs and with the compound of the formula (IV) ** (See formula) ** in which the reaction takes place in the presence of an imidazole of the formula (V) ** ( See formula) ** wherein the moiety R1 is an unsubstituted (C1-C12) alkyl or an unsubstituted benzyl.

Description

DESCRIPTION

Preparation process of 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazoM-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate methyl

The invention relates to an improved process for the preparation of 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] - Methyl 5-methylthiophene-3-carboxylate (known by the common name "thiencarbazone-methyl").

The herbicidal activity of substituted thien-3-ylsulfonylaminocarbonyltriazolinones is known from DE 199 33 260 A1 and from WO 01/05788 A1, in which priority is claimed from DE 199 33260 A1.

Selected substituted thien-3-ylsulfonylaminocarbonyltriazolinones, such as thiencarbazone-methyl, have especially good herbicidal activity.

Due to the good activity, the improvement of the preparation process of the above-mentioned herbicides, also with regard to the environmental compatibility of the preparation, was a constant effort of chemical research.

DE 19933260 A1 discloses, in addition to four additional process alternatives, with alternative (c), a process for the preparation of substituted thien-3-ylsulfonylaminocarbonyltriazolinones by reacting sulfonyl isocyanates with 5-methoxy-4-methyl-2,4 -dihydro-3H-1,2,4-triazol-3-one. In the case of these process alternatives mentioned above, the possibility of reacting substituted thiophene-3-sulfonyl chlorides with substituted triazolinones and metal (thio) cyanates, optionally in the presence of a reaction aid and if appropriate in the presence of a diluent, it is only outlined by a formula scheme (see De 19933260 A1, page 7), but not verified by a detailed example.

In connection with the alternatives of process (a) to (e), optional reaction aids are disclosed in DE 19933260 A1. For such reactions, these generally refer to acidic binders that can be used. The selection mentioned on page 9 of DE 19933260 A1 also comprises potassium tert-butylate as well as basic nitrogen compounds such as, for example, amines, including tributylamine and pyridines such as, for example, 2-methylpyridines, 3-methylpyridine, 5 -ethyl-2-methylpyridine, 2,6-dimethylpyridine

In contrast, imidazoles are not mentioned as reaction aids in DE 19933260 A1. In DE 102004063192 A1 a process is proposed starting from sulfonamide and phosgene to prepare the sulfonyl isocyanate using the alternative process described in DE 19933260 A1 (i.e. preparation of thiencarbazone-methyl by reaction of sulfonyl isocyanates with 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one).

However, the process disclosed in DE 102004063192 A1, due to the use of phosgene which is classified as highly toxic, is dangerous and therefore complicated and expensive.

In this context, the object of the invention is to provide an improved process for the preparation of substituted thien-3-ylsulfonylaminocarbonyltriazolinones, in particular thiencarbazone-methyl, that is, the compound of formula (I), in which the improved process It is intended to allow preparation of the thiencarbazone-methyl target compound in high purity and yield.

The objective is achieved by the process according to claim 1, for the preparation of the compound of formula (I)

reacting the compound of formula (II)

with a metal cyanate of the formula (III)

MeOCN (III),

in which Me is Li, Na, K or Cs, with the compound of formula (IV)

wherein the reaction takes place in the presence of an imidazole of formula (V)

(V),

wherein the moiety R ¹ is an unsubstituted (C ¹ -C ¹² ) alkyl or an unsubstituted benzyl.

Surprisingly, it has been found in the context of the process according to the invention that the use of alkyl-substituted imidazoles, in particular N-alkylimidazoles, enables the preparation of substituted thien-3-ylsulfonylaminocarbonyltriazolinones, in particular the preparation of 4 - [( Methyl 4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (thiencarbazone-methyl ), with a particularly high purity and yield.

Therefore, the invention is based on the finding that the compound of formula (I), thiencarbazone-methyl, under certain conditions, specifically, in the presence of a 1-substituted imidazole base or in the presence of a Base mixture containing 1-substituted imidazole base (N-alkylimidazole), can be prepared directly from 4-methoxycarbonyl-2-methylthiophene-3-sulfonyl chloride (compound of formula (II)) with high purity and yield.

Reaction scheme:

The above reaction scheme shows that when the reaction is carried out as a one-pot synthesis at the beginning of the reaction, a 4-component system is present.

In the case of a two-stage reaction regimen, the reagent 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one of Formula (IV) is only added to the mixture after formation of the sulfonyl isocyanate from compounds of formulas (II) and (III) in the presence of an N-alkylimidazole of formula (V).

The synthesis of the reagents, ie the synthesis of the compounds of the formula (II) and (IV) in the above reaction scheme, is disclosed in DE 19933260 A1. Compounds of formula (III) and (V) are commercially available.

Imidazoles substituted by an alkyl moiety at the 1-position (N-alkylimidazoles) are supposed to act particularly well as activators (= activating agents) and / or stabilizers in the formation of the sulfonyl isocyanate.

However, the core of the present invention relates to the surprising finding that metal cyanate selectively reacts with the sulfonyl group of the respective thiophene compound (with the methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate formula (II) in the above scheme) in the presence of an N-alkylimidazole of formula (V) to give a sulfonyl isocyanate, and that from this the substituted thien-3-ylsulfonylaminocarbonyltriazolinone (the target compound thiencarbazone-methyl (I) in the above reaction scheme) is subsequently formed.

The unexpected selectivity of the reaction represented in the scheme is that the triazolinone (IV) only reacts after the formation of the sulfonyl isocyanate further with it to give the thiencarbazonemethyl.

Furthermore, regarding the use of a metal cyanate in a chemical reaction, it is of fairly general concern that metal cyanates are strong bases (sodium cyanate (NaOCN), for example, has a pH of 10). At the same time, metal cyanates act as O-nucleophiles.

In the presence of an N-alkylimidazole, in particular in the presence of N-methylimidazole, the O-nucleophilicity of the metal cyanate used according to the invention surprisingly but particularly does not affect the course of the present reaction, that is, the yield and the selectivity of it.

This does not apply to the use of other basic nitrogen compounds, such as pyridines, picolines or 4- (dimethylamino) pyridine (DMAp), which can be considered as classical activators of carboxylic acid halides, for example. The same applies to the use of inorganic bases such as K ² CO ³ or potassium tert-butylate (KOtBu) which have also proven unsuitable.

For example, it has been verified for example that the yield of thiencarbazone-methyl when using the process according to the invention is unexpectedly high compared to the performance of the reaction using other alternative basic nitrogen compounds.

The process according to the invention is preferably carried out in the presence of an imidazole of the formula (V), in which the radical R ¹ is an unsubstituted alkyl (Ci-Ca) or an unsubstituted benzyl. Carrying out the process in the presence of an imidazole of the formula (V), in which the moiety R ¹ is a substituted alkyl (Ci-Ca) or a substituted benzyl is not preferred but is also within the scope of the invention.

The process according to the invention is carried out particularly preferably in the presence of an imidazole of the formula (V), in which the radical R ¹ is an unsubstituted (C ¹ -C ⁴ ) alkyl. Very particular preference is given to ^{unbranched (C 1} -C ⁴ ) alkyl, ie methyl, ethyl, n-propyl or n-butyl as R ¹ .

The process according to the invention is most preferably carried out in the presence of N-methylimidazole (NMI), that is to say when the radical R ¹ in formula (V) is methyl.

To prepare the compound of formula (I) by the process according to the invention, the reagents are preferably used in equimolar amount or in excess.

In general, for each mole of sulfonic acid chloride, i.e. the compound of formula (II), 1 to 2.5 moles are used, preferably 1 to 2 moles, especially preferably 1 to 1, 8 moles of the metal cyanate of the formula MeOCN (III). However, the use of larger excesses of the compound of formula (III) is also within the scope of the invention.

In a preferred embodiment, Me in the compounds of the formula MeOCN (III) is Na or K. The most preferred metal cyanate in the process according to the invention is NaOCN. Furthermore, generally for each mole of sulfonic acid chloride, that is, of the compound of formula (IV) (5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3- one) are similarly used 1 to 2 moles, preferably 1 to 1.5 moles, especially preferably 1 to 1.1 moles.

However, the use of larger excesses of the compound of formula (IV) is also within the scope of the invention.

The process is carried out in an organic solvent, in which the nonpolar and polar solvents are appropriate.

Non-polar solvents include toluene, chlorobenzene, xylene, methyl tert-butyl ether, methyl isopropyl ether, ethyl acetate, isopropyl acetate and butyl acetate.

Especially preferred polar solvents are selected from the group consisting of acetonitrile, butyronitrile, tetrahydrofuran (THF), methyl-THF, dimethoxyethane, sulfolane, dimethylformamide, and dimethylacetamide.

Most preferred as a solvent are acetonitrile and THF.

Mixtures of different solvents can also be used.

The reaction of the reagents is preferably carried out in a temperature range from 20 ° to 110 ° for a duration (reaction time, reaction duration) of 3 hours to 24 hours.

Very particular preference is given to the reaction of the reactants in a temperature range of 30 ° to 90 °. The reaction of the reagents is more preferably carried out in a temperature range of 50 ° to 80 °.

Another aspect of the invention relates to the use of an imidazole of formula (V)

(V),

wherein the moiety R ¹ is an unsubstituted (C ¹ -C ¹² ) alkyl or an unsubstituted benzyl, to prepare the compound of formula (I)

Preference is given to the use of an imidazole of formula (V), wherein R ¹ is unsubstituted (C ¹ -C ⁴ ) alkyl.

Particular preference is given to the use of an imidazole of the formula (V), in which R ¹ is an unsubstituted ^{and unbranched (C 1} -C ⁴ ) alkyl, i.e., methyl, ethyl, n-propyl or n- butyl.

Most preferred is the use of an imidazole of formula (V), in which R ¹ is methyl.

Examples

The preparation process according to the invention can be carried out as a one-pot process or as a two-stage reaction.

In the one-pot procedure, all chemicals are mixed in an organic solvent and then heated with stirring. To better control the exotherm of the reaction, it is also advisable to initially charge the reagents of formulas (III), (IV) and (V) in acetonitrile, for example, and then slowly measure the sulfonyl chloride of formula (II) as a solution at reaction temperature.

During the reaction, the active ingredient or the salt thereof precipitates from the reaction mixture and can then be simply filtered.

It is particularly advantageous at the end of the reaction to add to the mixture an inorganic base such as LiOH, K ² CO ³ , NaHCO ³ , NaOH, Na ² CO ³ , CaCO ³ or KOH to isolate the active principle as an insoluble Li salt, Na, K or Ca. The use of NaHCO ³ is preferred. In this way, it is possible to isolate the active principle with a very high purity.

The amount of base to be used depends on the amount of metal cyanate used in carrying out the reaction. When only 1 equivalent (eq) of NaOCN is used, then 1 eq. base is correspondingly required to convert the active ingredient completely to the salt (Example 1). For example, if 2 eq. of metal cyanate, for example, 2 eq are used. of NaOCN to carry out the reaction, no additional base is required (see example 3).

By treating the salt with an acid (eg HCl, H ² SO ⁴ ), the active ingredient is released and isolated after filtration. It is also possible to first react the compound of the formula (II) with MeOCN in the presence of the compound of the formula (V) to produce the sulfonyl isocyanate of the formula (VI). Then, in a second stage, the sulfonyl isocyanate, optionally without prior isolation, is reacted with 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one of the formula (IV).

Analysis, identification and determination of the sulfonyl isocyanate content after step 1 is based on derivatization with methanol to give the corresponding carbamate of formula (VII).

If necessary, the isocyanate can be isolated and purified by vacuum distillation.

TABLE 1

The above table confirms that the yield of thiencarbazone-methyl when using the process according to the invention and using N-butylimidazole and N-methylimidazole is unexpectedly high compared to other nitrogenous bases. In contrast, in the case of comparative use of nitrogen-based tributylamine, the thiencarbazone-methyl target product is detectable in a low% range by liquid chromatography (LC). When using potassium tert-butylate acid binder (KOtBu), product detection is not even possible.

Synthesis examples

Example 1

Methyl 4 - [(4,5-Dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (procedure of a container)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 6.5 g of NaOCN, 12.9 g of N-methylimidazole and 12.9 g of 5-methoxy-4-methyl- 2,4-dihydro-3H-1,2,4-triazol-3-one are initially charged in 200 ml of acetonitrile and heated at 70 ° C. The mixture was heated at this temperature with stirring for 12 h and cooled to 20 ° C.

8.5 g of NaHCO ³ were added to the mixture and the suspension was further stirred at 20 ° C for 3 h. The precipitate was filtered, washed with 50 ml of 10% HCl and 100 ml of water and dried at 50 ° C. This gave 31.6 g of 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5- Methyl methylthiophene-3-carboxylate, 80% of theory with a melting point of 201 ° C, and a purity of 99%.

Example 2

Methyl 4 - [(4,5-Dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (procedure of a container)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 11.7 g of NaOCN, 8.2 g of N-methylimidazole and 12.9 g of 5-methoxy-4-methyl-2, 4-dihydro-3H-1,2,4-triazol-3-one are initially charged in 220 ml of acetonitrile and heated to 70 ° C. The mixture was heated at this temperature with stirring for 18 h and cooled to 20 ° C. 1.7 g of NaHCO ³ were added to the mixture and the suspension was further stirred at 20 ° C for 2 h. The mixture was heated to 60 ° C, the precipitate was filtered and washed with 50 ml of acetonitrile. After that, the precipitate was washed with 70 ml of ^{20% H 2} SO ⁴ , 100 ml of hot water (70 ° C) and 50 ml of acetone and dried at 50 ° C. This gave 31.4 g of 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5- Methyl methylthiophene-3-carboxylate, 79% of theory with a purity of 98%.

Example 3

Methyl 4 - [(4,5-Dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (procedure of a container)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 13 g of NaOCN, 12.9 g of N-methylimidazole and 12.9 g of 5-methoxy-4-methyl-2,4- dihydro-3H-1,2,4-triazol-3-one are initially charged in 200 ml of acetonitrile and heated to 70 ° C. The mixture was heated at this temperature with stirring for 12 h and cooled to 20 ° C.

The precipitate was filtered, washed with 50 ml of 10% HCl and 100 ml of water and dried at 50 ° C. This gave 33.6 g of 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5- Methyl methylthiophene-3-carboxylate, 84.4% of theory with a purity of 98%.

Example 4

Methyl 4 - [(4,5-Dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (two-stage procedure)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 6.5 g of NaOCN, 12.9 g of N-methylimidazole were initially charged into 150 ml of acetonitrile and the mixture was heated to 50 ° C, for 4 h. The suspension was filtered through a glass frit under argon and 12.5 g of 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one were added to the filtrate. . The mixture was then heated to 70 ° C for ⁸ hours and cooled to 20 ° C.

⁸ g of NaHCO ³ and 1 ml of water were added to the mixture and the suspension was stirred for a further 3 h. The precipitate was filtered, washed with 50 ml of 10% HCl and 100 ml of water and dried at 50 ° C. This gave 29.6 g of 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5- Methyl methylthiophene-3-carboxylate, 75.6% of theory with a melting point of 201 ° C, and a purity of> 99%.

Example 5

Methyl 4- [(4,5-Dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (two-stage procedure)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 11.7 g of NaOCN, 12.3 g of N-methylimidazole were initially charged into 150 ml of acetonitrile and the mixture was heated to 50 ° C, for 4 h. The suspension was filtered through a glass frit under argon and 12.5 g of 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one were added to the filtrate. . After that, the mixture was heated to 70 ° C for 12 hours and cooled to 20 ° C.

^{1.7 g of NaHCO 3} and 1 ml of water were added to the mixture and the suspension was stirred for a further 3 hours. The precipitate was filtered, washed with 50 ml of 10% HCl and 100 ml of water and dried at 50 ° C. This gave 30.5 g of 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl) carbonyl) sulfamoyl] -5- Methyl methylthiophene-3-carboxylate, 77% of theory and a purity of 98%.

Example 6

Methyl 4- (Methoxycarbonylsulfamoyl) -5-methylthiophene-3-carboxylate

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 6.5 g of NaOCN, 12.9 g of N-methylimidazole are They were initially charged in 150 ml of acetonitrile and the mixture was heated at 50 ° C, for 4 h. The suspension was filtered through a glass frit under argon and 30 ml of methanol was added. After 1 hour, the solution was fully concentrated and the precipitate was washed with water and dried. This gave 24 g of methyl 4- (methoxycarbonylsulfamoyl) -5-methylthiophene-3-carboxylate (1H NMR: (d6 DMSO) 2.72 (s), 3.62 (s), 3.79 (s), 8.01 (s), 12.01 (s) ppm).

Claims (15)

1. Process for preparing the compound of formula (I)

reacting the compound of formula (II)

with a metal cyanate of the formula (III) MeOCN (III) where Me is Li, Na, K or Cs and with the compound of formula (IV)

wherein the reaction takes place in the presence of an imidazole of formula (V)

(V), wherein the moiety R ¹ is an unsubstituted (C ¹ -C ¹² ) alkyl or an unsubstituted benzyl. 2. Process for preparing compounds of formula (I) according to claim 1, characterized in that R ¹ is an unsubstituted (C ¹ -C ⁶ ) alkyl or an unsubstituted benzyl. 3. Process for preparing compounds of formula (I) according to claim 2, characterized in that R ¹ is an unsubstituted (C ¹ -C ⁴ ) alkyl. 4. Process for preparing compounds of formula (I) according to claim 3, characterized in that R ¹ is methyl, ethyl, n-propyl or n-butyl. 5. Process for preparing compounds of formula (I) according to claim 4, characterized in that R ¹ is methyl. 6. Process for the preparation of compounds of the formula (I) according to one of claims 1 to 5, characterized in that Me in the compounds of the formula MeOCN (III) is Na or K. 7. Process for preparing compounds of formula (I) according to one of claims 1 to 6, characterized in that the reaction takes place in a polar solvent selected from the group consisting of acetonitrile, butyronitrile, tetrahydrofuran (THF), methyl-THF , dimethoxyethane, sulfolane, dimethylformamide and dimethylacetamide. 8. Process for preparing compounds of formula (I) according to one of claims 1 to 6, characterized in that the reaction takes place in a solvent mixture consisting of acetonitrile and THF. Process for preparing compounds of formula (I) according to one of Claims 1 to 8, characterized in that the reaction of the reagents takes place - in a temperature range from 20 ° to 110 ° and - in a reaction time of 3 hours to 24 hours. 10. Process for preparing compounds of formula (I) according to claim 9, characterized in that the reaction of the reagents takes place in a temperature range of 30 ° to 90 °. 11. Process for preparing compounds of formula (I) according to claim 10, characterized in that the reaction of the reagents takes place in a temperature range of 50 ° to 80 °. 12. Use of an imidazole of formula (V)

(V), wherein the radical R ¹ is an unsubstituted (C ¹ -C ¹² ) alkyl or an unsubstituted benzyl, for a process for preparing the compound of formula (I)

according to one of claims 1 to 9. 13. Use of an imidazole of formula (V) according to claim 12, characterized in that R ¹ is an unsubstituted (C ¹ -C ⁴ ) alkyl. 14. Use of an imidazole of formula (V) according to claim 13, characterized in that R ¹ is methyl, ethyl, n-propyl or n-butyl. 15. Use of an imidazole of formula (V) according to claim 14, characterized in that R ¹ is methyl.